Prostate cancer, a leading cause of cancer related deaths among men in the United States, is usually diagnosed in the sixth or seventh decades of life, which allows a large window for intervention to prevent disease progression. Clinical development of agents that can prevent prostate cancer could have a significant impact on morbidity and mortality for a large segment of population. This R21 application proposes preclinical studies to determine efficacy of Commiphora mukul extract (CME) for prevention of prostate cancer in vivo and to elucidate the mechanism of its anti-carcinogenic effect. Commiphora mukul has been used in the Indian Ayurvedic medicine practice for thousands of years for different ailments. A standardized formulation of Commiphora mukul (manufactured by GNC) is already in human use as a cholesterol-lowering agent (Gugulipid(R), 500 mg capsule standardized to 2.5% z-guggulsterone). Guided by the results of our preliminary studies, we hypothesize that CME may prevent prostate cancer due to its ability to cause G2/M phase cell cycle arrest and Bak/Bcl-xL mediated apoptosis. Studies proposed in specific aims 1 and 2 of this application will elucidate the mechanism by which CME causes G2/M phase cell cycle arrest and apoptosis induction in human prostate cancer cells, whereas studies in specific aim 3 will determine efficacy of CME for prevention of prostate carcinogenesis in vivo in TRAMP model. The results from proposed mechanistic studies may lead to identification of biomarker(s) optimization of CME-based chemopreventive regimens for prevention of prostate cancer. Determining efficacy of CME against prostate cancer in animal models is a prerequisite for initiation of clinical trials to determine its activity against human prostate cancers. PUBLIC HEALTH RELEVANCE: The long term goal of this preclinical research project is to develop a safe and effective strategy for prevention of human prostate cancer, which is a leading cause of cancer related deaths among men in the United States, using an Indian Ayurvedic medicine component [Commiphora mukul extract (CME)]. Studies proposed in this application will define the mechanism by which CME inhibits growth of human prostate cancer cells, which may lead to identification of biomarker(s) of CME response potentially useful in future clinical trials as well as optimization of CME-based regimens for prevention of prostate cancer, and determine efficacy of CME in vivo for prevention of prostate cancer in an animal model (TRAMP), which is a prerequisite for initiation of clinical trials to determine its activity against human prostate cancers.